title: GPNMB enhances bone regeneration by promoting angiogenesis and osteogenesis: potential role for tissue engineering bone.
abstract: Bone regeneration is a coordinated process involving the connection between blood vessels and bone cells. Glycoprotein non-metastatic melanoma protein B (GPNMB) is known to be vital in bone formation. However, the effect of GPNMB on bone regeneration and the underlying molecular mechanism are still undefined. Fibroblast growth factor receptor (FGFR)-mediating signaling is pivotal in bone formation and angiogenesis. Therefore, we assessed GPNMB function as a communicating molecule between osteoblasts and angiogenesis, and the possible correlation with FGFR-1 signaling. Recombinant GPNMB dose-dependently increased the differentiation of human bone marrow stromal cells (hBMSCs) into osteoblasts, as well as the mRNA levels of osteoblasts marker alkaline phosphatase (ALP) and osteocalcin (OCN). Furthermore, these increases depended on the activation of FGFR-1 signaling, as pretreatment with FGFR-1 siRNA or its inhibitor SU5402 dramatically dampened GPNMB-induced osteogenesis. Additionally, GPNMB triggered dose-dependently the proliferation and migration of human umbilical vein endothelial cells (hUVECs), FGFR-1 phosphorylation, as well as capillary tube and vessels formation in vitro and in vivo. Blocking FGFR-1 signaling dampened GPNMB-induced angiogenic activity. Following construction of a rodent cranial defect model, scaffolds delivering GPNMB resulted in an evident increase in blood vessels and new bone formation; however, combined delivery of GPNMB and SU5402 abated these increase in defect sites. Taken together, these results suggest that GPNMB stimulates bone regeneration by inducing osteogenesis and angiogenesis via regulating FGFR-1 signaling. Consequently, our findings will clarify a new explanation about how GPNMB induces bone repair, and provide a potential target for bone regeneration therapeutics and bone engineering.
authors.affiliation: Department of Orthopedics, Chinese PLA 171 Hospital, Jiangxi, 332000, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Hu
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Zhenjie
authors.initials: Z
authors.lastname: Xu
authors.forename: Hongdong
authors.initials: H
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D001861:Bone Regeneration / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics*; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics*; D010766:Phosphorylation; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D023822:Tissue Engineering
chemical_list: C503042:GPNMB protein, human; D008562:Membrane Glycoproteins; D017468:Receptors, Fibroblast Growth Factor; D015675:Osteocalcin; D000469:Alkaline Phosphatase
keywords: ANGIOGENESIS; BONE GENERATION; FGFR-1; GPNMB; OSTEOGENESIS